LYN

For other uses, see Lyn (disambiguation).

LYN
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1W1F, 1WA7, 3A4O
Identifiers
Aliases	LYN , LYN proto-oncogene, Src family tyrosine kinase, JTK8, p53Lyn, p56Lyn
External IDs	OMIM: 165120; MGI: 96892; HomoloGene: 55649; GeneCards: LYN; OMA:LYN - orthologs
Gene location (Human) Chr. Chromosome 8 (human) [1] Band 8q12.1 Start 55,879,835 bp [1] End 56,014,169 bp [1]
Gene location (Mouse) Chr. Chromosome 4 (mouse) [2] Band 4 A1|4 2.05 cM Start 3,678,115 bp [2] End 3,813,122 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte blood palpebral conjunctiva bone marrow nasal epithelium bone marrow cell appendix periodontal fiber granulocyte trabecular bone Top expressed in stroma of bone marrow granulocyte blood mesenteric lymph nodes Vasculature of brain spleen tibiofemoral joint right lung lobe left lung left lung lobe More reference expression data BioGPS n/a
Gene ontology Molecular function transmembrane transporter binding SH3 domain binding protein-containing complex binding kinase activity gamma-tubulin binding signaling receptor binding ATP binding protein kinase activity non-membrane spanning protein tyrosine kinase activity enzyme binding transferase activity platelet-derived growth factor receptor binding integrin binding protein binding glycosphingolipid binding protein tyrosine kinase activity nucleotide binding phosphoprotein binding ubiquitin protein ligase binding ephrin receptor binding phosphorylation-dependent protein binding Cellular component cytoplasm cytosol membrane extrinsic component of cytoplasmic side of plasma membrane mitochondrial intermembrane space perinuclear region of cytoplasm nucleus mitochondrial membranes membrane raft extracellular exosome Golgi apparatus plasma membrane postsynaptic density mast cell granule integrin alpha2-beta1 complex mitochondrial crista intracellular membrane-bounded organelle glutamatergic synapse postsynaptic specialization, intracellular component Biological process regulation of protein phosphorylation cellular response to extracellular stimulus cellular response to retinoic acid positive regulation of B cell receptor signaling pathway tolerance induction to self antigen regulation of mast cell activation regulation of cell adhesion mediated by integrin cellular response to heat response to amino acid hemopoiesis adaptive immune response regulation of erythrocyte differentiation cellular response to DNA damage stimulus positive regulation of Fc receptor mediated stimulatory signaling pathway platelet activation Fc-epsilon receptor signaling pathway protein phosphorylation regulation of B cell apoptotic process positive regulation of dendritic cell apoptotic process positive regulation of glial cell proliferation response to carbohydrate regulation of platelet aggregation negative regulation of cell population proliferation B cell receptor signaling pathway negative regulation of myeloid leukocyte differentiation dendritic cell differentiation Fc receptor mediated inhibitory signaling pathway Fc-gamma receptor signaling pathway involved in phagocytosis transmembrane receptor protein tyrosine kinase signaling pathway regulation of B cell receptor signaling pathway stimulatory C-type lectin receptor signaling pathway response to sterol depletion positive regulation of stress-activated protein kinase signaling cascade regulation of cytokine production response to insulin positive regulation of mast cell proliferation negative regulation of MAP kinase activity regulation of ERK1 and ERK2 cascade positive regulation of peptidyl-tyrosine phosphorylation erythrocyte differentiation protein autophosphorylation oligodendrocyte development regulation of mast cell degranulation positive regulation of phosphorylation viral process response to toxic substance negative regulation of protein phosphorylation Fc receptor mediated stimulatory signaling pathway growth hormone receptor signaling pathway via JAK-STAT phosphorylation immune system process regulation of release of sequestered calcium ion into cytosol positive regulation of tyrosine phosphorylation of STAT protein B cell homeostasis immune response-regulating cell surface receptor signaling pathway response to axon injury negative regulation of mast cell proliferation regulation of inflammatory response peptidyl-tyrosine autophosphorylation response to hormone regulation of monocyte chemotaxis leukocyte migration lipopolysaccharide-mediated signaling pathway histamine secretion by mast cell intracellular signal transduction response to organic cyclic compound negative regulation of intracellular signal transduction positive regulation of cell migration ephrin receptor signaling pathway negative regulation of toll-like receptor 2 signaling pathway T cell costimulation response to peptide hormone platelet degranulation blood coagulation positive regulation of phosphatidylinositol 3-kinase activity positive regulation of oligodendrocyte progenitor proliferation negative regulation of immune response positive regulation of cell population proliferation positive regulation of neuron projection development negative regulation of ERK1 and ERK2 cascade peptidyl-tyrosine phosphorylation negative regulation of B cell proliferation negative regulation of toll-like receptor 4 signaling pathway signal transduction innate immune response neuron projection development central nervous system development inflammatory response positive regulation of protein phosphorylation positive regulation of phosphatidylinositol 3-kinase signaling cell differentiation positive regulation of Ras protein signal transduction positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4067 17096 Ensembl ENSG00000254087 ENSMUSG00000042228 UniProt P07948 P25911 RefSeq (mRNA) NM_001111097 NM_002350 NM_001111096 NM_010747 RefSeq (protein) NP_001104567 NP_002341 NP_001104566 NP_034877 Location (UCSC) Chr 8: 55.88 – 56.01 Mb Chr 4: 3.68 – 3.81 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Tyrosine-protein kinase Lyn is a protein that in humans is encoded by the LYN gene. ^[5]

Lyn is a member of the Src family of protein tyrosine kinases, which is mainly expressed in hematopoietic cells, ^[6] in neural tissues ^[7] liver, and adipose tissue. ^[8] In various hematopoietic cells, Lyn has emerged as a key enzyme involved in the regulation of cell activation. In these cells, a small amount of LYN is associated with cell surface receptor proteins, including the B cell antigen receptor (BCR), ^{[9] [10]} CD40, ^[11] or CD19. ^[12] The abbreviation Lyn is derived from Lck/Yes novel tyrosine kinase, Lck and Yes also being members of the Src kinase family.

Function

Lyn has been described to have an inhibitory role in myeloid lineage proliferation. ^[13] Following engagement of the B cell receptors, Lyn undergoes rapid phosphorylation and activation. This activation initiates a cascade of signaling events mediated by Lyn phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAMs) of receptor proteins. This cascade leads to the recruitment and activation of other kinases, including Syk, phospholipase Cγ2 (PLCγ2), and phosphatidyl inositol-3 kinase. ^{[12] [14]} These kinases generate activation signals critical for proliferation, Ca²⁺ mobilization, and cell differentiation.

Lyn also plays an essential role in transmitting inhibitory signals by phosphorylating tyrosine residues within the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of regulatory proteins such as CD22, PIR-B, and FCγRIIb1. ITIM phosphorylation subsequently recruits and activates phosphatases including SHIP-1 and SHP-1, ^{[15] [16] [17] [18] [19]} leading to the attenuation of signaling pathways, downregulation of cell activation, and promotion of tolerance. In B cells, Lyn sets the threshold of signaling and maintains the balance between activation and inhibition, effectively functioning as a rheostat rather than a binary switch. ^{[20] [21] [22]}

LYN is reported to be a key mediator of estrogen-dependent suppression of human osteoclast differentiation, survival, and function. ^[23] It has also been implicated in the insulin signaling pathway, where activated Lyn phosphorylates insulin receptor substrate 1 (IRS1), promoting Glut-4 translocation to the membrane and enhancing glucose utilization. ^[24] Insulin receptor activation has been shown to increase Lyn autophosphorylation, suggesting a feedback loop. ^[25]

Lyn has been shown to protect against hepatocellular apoptosis and promote liver regeneration by preserving mitochondrial integrity. ^[26]

In pulmonary function, Lyn activation in pulmonary epithelium has been linked to improved barrier integrity and reduced edema. ^{[27] [28]} Lyn activation in alveolar phagocytes enhances bacterial phagocytosis and reduces pulmonary infections. ^{[29] [30]} Furthermore, Lyn activation has been shown to reduce pulmonary mucus hypersecretion. ^[31]

Clinical significance

As a drug target

HSP90 inhibitor NVP-BEP800 has been reported to affect Lyn kinase stability and inhibit the growth of B-cell acute lymphoblastic leukemias by interfering with NF-kappaB signaling. ^[32]

The allosteric activator of Lyn kinase Tolimidone (MLR-1023) is currently under Phase 2a clinical investigation for Type II diabetes, with promising results reported from studies conducted by Melior Discovery. ^{[33] [34] [35] [36]}

The insulin secretagogue glimepiride (Amaryl®) activates Lyn in adipocytes by disrupting lipid rafts, ^[37] potentially contributing to its extrapancreatic glycemic control effects. ^{[37] [38]} Tolimidone (MLR-1023), a small-molecule allosteric activator of Lyn kinase with an EC₅₀ of 63 nM, ^{[39] [40]} is under Phase 2a investigation for Type II diabetes. ^[33]

Pathology

Much of the current knowledge about Lyn has emerged from studies of genetically manipulated mice. Lyn deficient mice display a phenotype that includes splenomegaly, a dramatic increase in numbers of myeloid progenitors and monocyte/macrophage tumors. Biochemical analysis of cells from these mutants revealed that Lyn is essential in establishing ITIM-dependent inhibitory signaling and for activation of specific protein tyrosine phosphatases within myeloid cells. ^[13]

Mice that expressed a hyperactive Lyn allele were tumor free and displayed no propensity toward hematological malignancy. These mice have reduced numbers of conventional B lymphocytes, down-regulated surface immunoglobulin M and costimulatory molecules, and elevated numbers of B1a B cells. With age these animals developed a glomerulonephritis phenotype associated with a 30% reduction in life expectancy. ^[41]

Interactions

LYN has been shown to interact with:

• BCAR1, ^{[42] [43]}
• CD117, ^{[44] [45]}
• CD22, ^{[46] [47]}
• Cdk1, ^{[48] [49]}
• DOK1, ^{[44] [50]}
• EPOR ^[51]
• GPVI, ^[52]
• INPP5D, ^[53]
• IRS1, ^[24]
• LCP2, ^[54]
• MUC1, ^[55]
• NEDD9, ^[42]
• PLCG2, ^{[56] [57]}
• PPP1R15A, ^[58]
• PTPRC, ^[59]
• Syk, ^[60]
• TRPV4, ^[61]
• UNC119, ^[62]

See also

• Lyn-CD22-SHP-1 pathway

References

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61. Xu H, Zhao H, Tian W, Yoshida K, Roullet JB, Cohen DM (Mar 2003). "Regulation of a transient receptor potential (TRP) channel by tyrosine phosphorylation. SRC family kinase-dependent tyrosine phosphorylation of TRPV4 on TYR-253 mediates its response to hypotonic stress". The Journal of Biological Chemistry. 278 (13): 11520–11527. doi: 10.1074/jbc.M211061200 . PMID   12538589.
62. Cen O, Gorska MM, Stafford SJ, Sur S, Alam R (Mar 2003). "Identification of UNC119 as a novel activator of SRC-type tyrosine kinases". The Journal of Biological Chemistry. 278 (10): 8837–8845. doi: 10.1074/jbc.M208261200 . PMID   12496276.

Further reading

• Jouvin MH, Numerof RP, Kinet JP (Feb 1995). "Signal transduction through the conserved motifs of the high affinity IgE receptor Fc epsilon RI". Seminars in Immunology. 7 (1): 29–35. doi:10.1016/1044-5323(95)90005-5. PMID   7612892.
• Hibbs ML, Dunn AR (Mar 1997). "Lyn, a src-like tyrosine kinase". The International Journal of Biochemistry & Cell Biology. 29 (3): 397–400. doi:10.1016/S1357-2725(96)00104-5. PMID   9202419.
• Blasioli J, Goodnow CC (2002). "Lyn/CD22/SHP-1 and Their Importance in Autoimmunity". Current Directions in Autoimmunity. Vol. 5. pp. 151–160. doi:10.1159/000060551. ISBN   978-3-8055-7308-5. PMID   11826756.
• Greenway AL, Holloway G, McPhee DA, Ellis P, Cornall A, Lidman M (Apr 2003). "HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication". Journal of Biosciences. 28 (3): 323–335. doi:10.1007/BF02970151. PMID   12734410. S2CID   33749514.
• Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M (Apr 2004). "HIV/SIV escape from immune surveillance: focus on Nef". Current HIV Research. 2 (2): 141–151. doi:10.2174/1570162043484924. PMID   15078178.
• Joseph AM, Kumar M, Mitra D (Jan 2005). "Nef: "necessary and enforcing factor" in HIV infection". Current HIV Research. 3 (1): 87–94. doi:10.2174/1570162052773013. PMID   15638726.
• Stove V, Verhasselt B (Jan 2006). "Modelling thymic HIV-1 Nef effects". Current HIV Research. 4 (1): 57–64. doi:10.2174/157016206775197583. PMID   16454711.

External links

• Overview of all the structural information available in the PDB for UniProt : P07948 (Tyrosine-protein kinase Lyn) at the PDBe-KB .